AB0056 CYTOKINE-DIRECTED CELLULAR CROSSTALK IMPRINTS SYNOVIAL PATHOTYPES IN RHEUMATOID ARTHRITIS
Authors: M. Kugler, M. Dellinger, F. Kartnig, L. Müller, T. Preglej, L. Heinz, E. Simader, L. Göschl, S. Puchner, S. Weiss, G. Superi-Furga, J. S. Smolen, G. Steiner, D. Aletaha, H. Kiener, A. Tosevska, T. M. Karonitsch, M. Bonelli
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> The chronic inflammatory disease Rheumatoid Arthritis (RA) is characterized by synovial inflammation promoting cartilage and bone degradation when left untreated. Interaction between infiltrating immune cells, such as CD4+ T cells and activated fibroblast-like synoviocytes (FLS) might contribute to joint inflammation ultimately amplifying progressive joint destruction. <h3>Objectives</h3> To elucidate the interaction of stimulated FLS and CD4+ T cells within an inflammatory environment and to define its impact on synovial inflammation. <h3>Methods</h3> To define the effect of inflammatory mediators, FLS were stimulated with different pro- and anti-inflammatory cytokines. Transcriptomic changes were measured using RNA sequencing (RNA-seq). Co-cultures of cytokine pre-treated FLS and fluorescence activated cell sorting (FACS)-purified naïve CD4+ T cells were established. Using high-content fluorescence microscopy combined with bioinformatic image analysis, cell-cell interactions were visualized and quantified. The consequence of FLS co-culturing on CD4+ T-cell development was addressed by flow cytometry of re-isolated CD4+ T-cells. <h3>Results</h3> RNA-seq on cytokine-stimulated FLS revealed cytokine-specific gene expression profiles. In line, we observed cytokine-specific patterns of interaction with CD4+ T-cells which could be further observed in flow cytometry data of T cell activation, proliferation and differentiation. Cytokine-stimulated FLS signatures could be detected in transcriptomic data of RA patient synovial tissue samples. <h3>Conclusion</h3> In this study, we highlight the role of FLS in orchestrating inflammation-associated synovial tissue remodeling and how cytokine induced CD4+ T cells – FLS interactions impact on T-cell development. <h3>References</h3> [1]Zhang F, Wei K, Slowikowski K, Fonseka CY, Rao DA, Kelly S, et al. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat Immunol. 2019. [2]Smolen JS, Aletaha D, Barton A, Burmester GR, Emery P, Firestein GS, et al. Rheumatoid arthritis. Nat Rev Dis Primers. 2018;4:18001. [3]Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. The Lancet. 2016;388(10055):2023-38. [4]Lewis MJ, Barnes MR, Blighe K, Goldmann K, Rana S, Hackney JA, et al. Molecular Portraits of Early Rheumatoid Arthritis Identify Clinical and Treatment Response Phenotypes. Cell Rep. 2019 Aug 27;28(9):2455-2470. [5]Rivellese F, Surace AEA, Goldmann K, Sciacca E, Çubuk C, Giorli G, et al. R4RA collaborative group. Rituximab versus tocilizumab in rheumatoid arthritis: synovial biopsy-based biomarker analysis of the phase 4 R4RA randomized trial. Nat Med. 2022 Jun;28(6):1256-1268. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> Maximilian Kugler: None declared, Mirjam Dellinger: None declared, Felix Kartnig: None declared, Lena Müller: None declared, Teresa Preglej: None declared, Leonhard Heinz: None declared, Elisabeth Simader: None declared, Lisa Göschl: None declared, Stephan Puchner: None declared, Sebastian Weiss: None declared, Giulio Superi-Furga: None declared, Josef S. Smolen Consultant of: AbbVie, Astra-Zeneca, Lilly, Novartis, Amgen, Astro, Bristol-Myers Squibb, Celgene, Celltrion, Chugai, Gilead, ILTOO, Janssen, Merck Sharp &amp; Dohme, Novartis-Sandoz, Pfizer, Roche, Samsung and UCB, Grant/research support from: AbbVie, Astra-Zeneca, Lilly, Novartis, Amgen, Astro, Bristol-Myers Squibb, Celgene, Celltrion, Chugai, Gilead, ILTOO, Janssen, Merck Sharp &amp; Dohme, Novartis-Sandoz, Pfizer, Roche, Samsung and UCB, Günter Steiner: None declared, Daniel Aletaha Consultant of: AbbVie, Amgen, Lilly, Merck, Novartis, Pfizer, Roche, Sandoz, Grant/research support from: AbbVie, Amgen, Lilly, Merck, Novartis, Pfizer, Roche, Sandoz, Hans Kiener: None declared, Anela Tosevska: None declared, Thomas Maria Karonitsch: None declared, Michael Bonelli Consultant of: Eli-Lilly, Grant/research support from: Galapagos.